Background/Purpose: Although data are conflicting with regard to the clinical utility of MTX polyglutamates (PGs) measurements as a predictor of the efficacy or toxicity in the treatment of rheumatoid arthritis (RA), it is considered to be essential for the therapeutic effect to achieve necessary concentrations of intracellular MTX-PGs. However, there is no universally accepted method of the optimal schedule for dose initiation and escalation. The higher starting dosage and faster increasing schedule is considered to be beneficial so far. In Japan, the officially approved dosage of MTX for RA treatment had been fixed up to 8mg/wk from 1996 to 2011, whereas the maximum doses of 20 to 30mg/wk were commonly used in the rest of world. As a result, we have very unique experience of extra-low-dose MTX (ExLD-MTX) treatment for RA. In this report, we evaluate the efficacy of ExLD-MTX treatment for RA, and we also investigate the concentrations of intracellular MTX-PGs after ExLD-MTX treatment.

Methods: RA cases treated with ExLD-MTX (n=133) were retrospectively investigated. After 12 months of the treatment, the rates of achieving remission criteria and of withdrawing from the initial treatment were calculated. Next, the concentrations of MTXGlu1–7 in red blood cell (RBC) lysates of 91 patients receiving long-term oral ExLD-MTX were quantitated with using HPLC method.

Results: After 12 months of ExLD-MTX treatment (mean MTX dosage: 6.68±1.72 mg/wk), 72.2% of cases were still maintained with the same treatment. The remission criteria for DAS28 (<2.6) were achieved 31.4% of patients, which is comparable to those of MTX monotherapy arm (mean MTX dosage: 16.9mg/wk) in PREMIER study. The rates of withdrawal because of adverse events and of insufficient efficacy were 2.2% and 25.6% in ExLD-MTX group, while 7.4% and 17.9% in MTX monotherapy arm in PREMIER study. The analysis of intracellular MTX-PG after ExLD-MTX treatment revealed distinct distribution of MTX-PG subtypes, i.e., 88.2±19.5% of MTX-PG was MTX-PG6-7, whereas the rate of MTX-PG6-7 was reported to be less than 1% after conventional MTX treatments. Although it did not reach statistical significance, the total concentrations of MTX-PG1-7 (nmoles/ 1g of Hb) after ExLD-MTX treatment were 8.3±3.8 (range: 3.3-15.4) in the DAS<2.6 group and 6.55±4.25 (range: 1.7-17.6) in the DAS>3.2 group. The percentages of low MTX-PG1-7 concentration (<5.0 nmoles/1g of Hb) were 7.7% in the DAS<2.6 group versus 44.8% in the DAS>3.2 group.  

Conclusion: Although the higher starting dosage and faster increasing schedule for MTX has been considered to be better, we found that the efficacy of ExLD-MTX treatment is comparable to conventional MTX treatments. Since MTX exposure was known to induce up-regulation of folylpolyglutamate hydrolase, which removes glutamic acid from MTX-PG, the ExLD-MTX treatment could be favorable for accumulation of the longer-chain MTX-PG. Although it seems to be beneficial to escalate the MTX dosage for some of patients with active disease (DAS>3.2) after ExLD-MTX treatment, a majority of them may have already sufficient MTX-PG concentration to predict its maximal efficacy. Our findings prompt a re-evaluation of the conventional methods for dose initiation and escalation of MTX

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-higher-and-faster-increasing-schedule-of-methotrexate-may-not-be-the-best-the-accumulation-of-intracellular-longer-chain-methotrexate-polyglutamates-was-facilitated-by-the-extra-low-dose-methotre/